KR20160023816A - Use of eribulin and lenvatinib as combination therapy for treatment of cancer - Google Patents

Abstract

The present invention provides methods and compositions used to treat diseases associated with excessive cell proliferation such as cancer.

Description

[0001] The present invention relates to the use of eribulin and < RTI ID = 0.0 > lenvatinib < / RTI > as a combination therapy for cancer therapy,

Cancer is used to describe a variety of diseases characterized by a specific type of uncontrolled, malignant cells. Cancer begins in tissues that contain cells, and can be treated by surgery, radiation therapy, or other topical treatments if the cancer has not metastasized to other tissues at diagnosis. However, if there is evidence that cancer has metastasized from the tissue of the organ, generally other treatment methods are used. In fact, since it is impossible to determine the degree of metastasis, a systematic approach to treatment is needed. Such approaches include the administration of a chemotherapeutic agent that inhibits the growth of rapidly dividing cells, such as cancer cells.

Halichondrin B is a structurally complex macrocyclic compound that was first extracted from the sea surface, Halichondria okadai, and has been found to contain axinella sp. Phakellia carteri sp. And Lissodendoryx sp were also extracted. The synthesis of halicondrine B was published in 1992 (Aicher et al., J. Am. Chem. Soc. 114: 3162-3164, 1992). Halicondrine B inhibits in vitro tubulin polymerization, microtubule assembly, beta S-tubulin cross-linking, GTP and vinblastine binding to tubulin and tubulin-dependent GTP hydrolysis . These halocondrine B molecules have anticancer activity in in vitro and in vivo. Halicondrine B analogs with anticancer activity are disclosed in U.S. Patent No. 6,214,865.

Eribulin is a synthetic analog of halocondrin B, also known as ER-086526, and the compound numbers are CAS number 253128-41-5 and US NCI designation number NSC-707389. The eribulin mesylate (marketed under the name HALAVEN®, also known as E7389) is a treatment for breast cancer patients who received at least two chemotherapy regimens for the treatment of metastases using anthracycline and taxane Is a drug approved for.

The chemical name of the eriburin mesylate salt is (2R, 3R, 3aS, 7R, 8aS, 9S, 10aR, 11S, 12R, 13aR, 13bS, 15S, 18S, 21S, 24S, 26R, Bis (methylene) -11,15,18,21: 24,28-triepoxy-2,6-dihydroxypropyl] hexacoshydro-3-methoxy- Furo [3,2-i] furo [2 ', 3': 5,6] pyrano [4,3-b] [l, 4] dioxacyclopentacosin-5 (4H) -one, methanesulfonate (salt), the structure of which is as follows:

 .

E7080 (lenvatinib mesylate) is an inhibitor of complex receptor tyrosine kinases (such as receptor tyrosine kinases involved in neovascularization and tumor growth). Complex receptor tyrosine kinases include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor receptor (PDGFRα), KIT, and RET proto-oncogene receptors. The compound is CAS number 857890-39-2 (or 417716-92-8). The chemical name of the renatintib mesylate is 4- [3-chloro-4 - [[(cyclopropylamino) carbonyl] amino] phenoxy] -7-methoxy-6-quinolinecarboxamide, methanesulfonate 1-yl) -7-methoxyquinoline-6-carboxamide, and N- {4 - [(6- Carbamoyl-7-methoxyquinolin-4-yl) oxyl-2-chlorophenyl} -N'-cyclopropylurea monomethanesulfonate]. The structural formula of lenbital nib mesylate is as follows:

[Summary of the Invention]

The present invention is based on the fact that the combination of eribulin and lenbactin exhibits an improved anti-cancer effect (e. G. Synergistic effect). Accordingly, the present invention provides the use of a combination of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulinyl mesylate) and lenbactin (or a pharmaceutically acceptable salt thereof, such as lenbital nisylate) And their use as therapeutic agents.

Thus, the present invention provides a method for treating a subject (e. G., A human patient) who is at risk of developing cancer or having cancer. The method of the present invention comprises the steps of (i) administering eribulin or a pharmaceutically acceptable salt thereof, such as eribulinyl mesylate, and (ii) lenbatinib or a pharmaceutically acceptable salt thereof, ) To the subject. The present invention also provides the use of a medicament for treating a subject and the use of a medicament preparation material. Descriptions of all the methods described below can be applied to such applications.

The subject will be diagnosed with cancer, undergo treatment, or will undergo recovery after treatment. Also, the cancer may be a primary tumor, a metastasis, and / or a solid cancer. The cancer may be selected from the group consisting of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colon cancer, ovarian cancer, endometrial cancer, skin cancer (e.g. melanoma), prostate cancer, brain cancer, head and neck cancer, Lymphoma, thyroid cancer, bone cancer (osteosarcoma), and fibrosarcoma.

Eribulin or a pharmaceutically acceptable salt thereof (for example, eribulinyl mesylate) is intravenously infused, and can be administered, for example, for about 1 minute to about 20 minutes or for about 2 minutes to about 5 minutes. In addition, eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulinyl mesylate) may be administered in an amount of about 0.1 mg / m ² to about 20 mg / m ² , or about 1.4 mg / m ² or 1.1 mg / m ² . ≪ / RTI > Also, eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulinyl mesylate) may be administered once a day on day 1 and day 8 of the 21 day cycle.

Rennartipine or a pharmaceutically acceptable salt thereof (e.g., lenbital nimethylsate) may be orally administered, for example, in an amount of about 0.1 mg to about 100 mg, or about 4 mg to about 24 mg. For example, renatintib or a pharmaceutically acceptable salt thereof (e.g., lanvatibm mesylate) can be administered by mail.

Eribulin or a pharmaceutically acceptable salt thereof (for example, eribulinyl mesylate), and lenbatimib or a pharmaceutically acceptable salt thereof (for example, lenbatinib mesylate) can be administered simultaneously or sequentially.

Treatment according to the method of the present invention comprises: (i) reducing the number of cancer cells; (Ii) reduce the tumor volume; (Iii) increase the tumor regression rate; (Iv) reducing or slowing cancer cell infiltration into organs; (V) reducing or slowing the metastasis; (Vi) reducing or inhibiting tumor growth; (Viii) inhibiting or delaying cancer development and / or recurrence, and / or prolonging the disease-free or tumor-free survival time; (Iii) increase overall survival; (Ⅸ) reduce the frequency of treatment; And / or (x) one or more symptoms associated with cancer.

The present invention also relates to a method of reducing the tumor size of a subject. The method comprises administering to the subject a composition comprising (i) eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulinyl mesylate), and (ii) lenbatinib or a pharmaceutically acceptable salt thereof, ). ≪ / RTI > The invention also encompasses the use of a therapeutic agent to reduce the size of a tumor in the subject.

On the other hand, the present invention provides a kit for use in treating cancer of a subject, decreasing tumor size, or increasing an immune response to a tumor. Said kit comprising (i) eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulinyl mesylate), and (ii) lenbatinib or a pharmaceutically acceptable salt thereof, such as lenbatinib mesylate, . Optionally, the therapeutic agent is present in a dosage form.

Other features of the invention will be apparent from the following detailed description, drawings and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating cancer comprising administering eribulin and lenbatinib (or a pharmaceutically acceptable salt thereof, such as a mesylate salt). The present invention also provides their use as cancer treating agents or their use as preparation substances. As in the following examples, erbiline mesylate and lanbactin mesylate were improved in anticancer effect when administered in combination. According to one embodiment of the invention, combination therapy has resulted in tumor regression. Thus, cancer treatment administering eribulin and lenbatimib (or a pharmaceutically acceptable salt thereof, such as a mesylate salt), according to the methods of the present invention, can be used to (i) reduce the number of cancer cells; (Ii) reduce the tumor volume; (Iii) increase the tumor regression rate; (Iv) reducing or slowing cancer cell infiltration into organs; (V) reducing or slowing the metastasis; (Vi) reducing or inhibiting tumor growth; (Viii) inhibiting or delaying cancer development and / or recurrence, and / or prolonging the disease-free or tumor-free survival time; (Iii) increase overall survival; (Ⅸ) reduce the frequency of treatment; And / or (x) one or more symptoms associated with cancer.

Pharmaceutical compositions, methods of use and methods of manufacture

Methods for the synthesis of eribulin (and its pharmaceutically acceptable salts, such as eriburine mesylate) are described in U.S. Patent Nos. 6,214,865; U.S. Patent No. 7,982,060; U.S. Patent No. 8,350,067; And U.S. Patent No. 8,093,410, each of which is incorporated herein by reference. Rebin'tanib (and its pharmaceutically acceptable salts, such as lenbatinib mesylate) and methods for its synthesis are disclosed in U.S. Patent No. 7,612,092, which is incorporated herein by reference.

As noted above, eribulin and / or lenbactin may optionally be used in the form of a salt. The salt may be used in the form of an inorganic acid salt or an organic acid salt, but the form of the salt is not particularly limited. For example, the salt may be selected from the group consisting of methanesulfonate (eribulinyl mesylate or lenbital nemesylate), hydrochloride, sulfate, citrate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, superphosphate, isonicotinate, But are not limited to, acetate, lactate, salicylate, stannate, pantothenate, ascorbate, succinate, maleate, fumarate, gluconate, saccharate, formate, benzoate, glutamate, ethanesulfonate, benzenesulfonate , p-toluene sulfonate, and pamoate.

Pharmaceutical compositions comprising eribulin or lenbitalinib (or a pharmaceutically acceptable salt thereof, such as a mesylate salt) can be prepared using methods known in the art (see the above-mentioned patents). Pharmaceutical compositions for use in the present invention may be prepared, for example, using physiologically acceptable diluents, carriers, additives or stabilizers (Remington's Pharmaceutical Sciences (20th edition), ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, ), Or by mixing the active ingredient (s) with the active ingredient (s). The acceptable diluent includes water and saline, optionally a buffer such as phosphoric acid, citric acid or other organic acids; Antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid; (Having less than about 10 residues) low molecular weight polypeptides; Proteins such as blood albumin, gelatin or immunoglobulin; Hydrophilic polymers such as polyvinylpyrrolidone; Amino acids such as glycine, glutamine, asparagine, arginine, or lysine; Monosaccharides, disaccharides or other carbohydrates including glucose, mannose or dextrin; Chelating agents such as EDTA; Sugar alcohols such as mannitol or sorbitol; Salt-forming counterion such as sodium; And / or non-ionic surfactants such as TWEEN ^TM , PLURONICS ^TM , or PEG.

Alternatively, the formulation of the present invention may comprise a pharmaceutically acceptable preservative. According to one example, the preservative concentration is between 0.1% and 2.0% v / v. Suitable preservatives include those known in the art and include, for example, benzyl alcohol, phenol, m-cresol, methyl paraben, and propyl paraben. In addition, eribulin and / or lenbactinib (or pharmaceutically acceptable salts thereof, such as mesylate salts) preparations may optionally contain a pharmaceutically acceptable salt, such as sodium chloride, at a physiological concentration . Thus, according to one embodiment of the present invention, eribulin (or a pharmaceutically acceptable salt thereof, such as eribulinyl mesylate) is formulated with 0.9% sodium chloride injection (USP). According to another example of the present invention, lenbatinib (or a pharmaceutically acceptable salt thereof, for example, lenbatinib mesylate) is formulated into an oral preparation such as a liquid, a tablet or a capsule.

According to one embodiment of the present invention, the above-mentioned agents can be administered parenterally. Thus, the medicament may be administered intravenously, intra-tumoral, peri-tumoral, intra-arterial, intra-dermal, intra-vesical ), Ophthalmic, intramuscular, intradermal, intraperitoneal, pulmonary, subcutaneous, and administration via the transdermal route, and the like. . Other routes may be used such as transmucosal, transdermal, inhalation, intravaginal, rectal and oral administration.

The dosage of eribulin and / or lenbactinib (or a pharmaceutically acceptable salt thereof, such as a mesylate salt) may be varied depending on the subject disease, drug delivery method, etc., as well as age, sex, weight, It can be significantly different. The drug is administered in an amount and manner to obtain an effect (e. G., Tumor reduction; or (i) - (x) effect). The amount of drug results in one or more additional or synergistic effects in cancer treatment (e.g., tumor reduction).

The drug may be administered to the patient simultaneously or sequentially (e. G., Prior to administration of lenbactin (or a pharmaceutically acceptable salt thereof, such as lenbatinib mesylate) Or a pharmaceutically acceptable salt thereof) or vice versa). Many therapies are applied to chemotherapy. For example, the treatment is repeated after one cycle (for example, 1-4 weeks) during which the patient has overcome side effects after administration of the drug (or drugs). In general, the number of administrations of eribulin (or a pharmaceutically acceptable salt thereof, such as an eriburyl mesylate) and / or lenbactin (or a pharmaceutically acceptable salt thereof, such as lanthabine mesylate) 8 times, for example, 4-7 times or 6 times. You may take all two drugs, or you may only take one of the medications (or all) of your treatment.

Thus, for example, Erie, called a day dose of (or Erie called mesylate chemical to allow its pharmaceutically acceptable salt, such as a) is 0.001 mg / m2 to about 100 mg / m ² (e.g., about 0.01 mg / m ² to about 50 mg / m ^2, 0.1 to about 5 mg / m ^2, or from about 0.7 mg / m ² to about 1.5 mg / m ^2, or a single dose within this range (e.g., 1.4, or it can be 1.1 mg / m ² )). Drugs may be taken once a day, once a week, once a month or once a year, or one or more times a day, a week, a month, or a year. For example, according to the one-dose method, the drug is administered once a day on days 1 and 8 of the 21-day cycle. According to other dosing regimens, the drug is administered once a day on days 1, 8 and 15 of the 28-day cycle. The drug can be taken for 1 minute to 1 hour (or longer), for example 2-5 minutes.

More specifically, the recommended dose of eriburin mesylate is intravenously administered at 1.4 mg / m < ² > for ² to 5 minutes on days 1 and 8 on a 21 day cycle. For patients with mild hepatic impairment (Child-Pugh A), the recommended dose is intravenous administration of 1.1 mg / m ² for 21 days on days 1 and 8 and 2-5 minutes on days 8, For patients with moderate hepatic impairment (Child-Pugh B), the recommended dose of eribulinyl mesylate is 0.7 mg / m ² for ² to 5 minutes on days 1 and 8 on a 21-day cycle . Also, in patients with moderate renal impairment (creatinine clearance 30-50 mL / min), the recommended dose of eribulinyl mesylate is 1.1 for two days on days 1 and 8 on day 21 mg / m < ^{2 &} gt ;. Another dosage regimen is intravenous administration of 1.1 mg / m ² for 2-5 minutes on days 1, 8 and 15 in a 28 day cycle.

The daily dose of adult rennettinib (or a pharmaceutically acceptable salt thereof, such as lenbatinib mesylate) is not particularly limited and may be, for example, about 0.1 mg to about 100 mg, for example, about 4 mg to about 24 mg, or a single dose within these ranges (e.g., 15 mg). The drug may be taken once a day, once a week, once a month or once a year, or one or more times a day, one week, one month, or one year. For example, the drug may be taken once a day on days 1 and 8 of the 21 day cycle. Or the drug on days 1, 8, and 15 of a 28 day cycle; Or on days 1, 8, 15 and 22 of the 35-day cycle once a day. Or the medicament may be administered once a day for a cycle of administration of eribulin (or a pharmaceutically acceptable salt thereof, such as an eribulin mesylate) and, optionally, an eribulin (or a pharmaceutical composition thereof, such as eribulin mesylate) Lt; / RTI > acceptable salt) may be administered daily during an additional dosing cycle. In addition, renvatinib (or a pharmaceutically acceptable salt thereof, such as a lanthabine mesylate) may be administered periodically (daily, weekly or biweekly) followed by one or more eribulins Followed by a treatment cycle, optionally followed by treatment for several weeks, several months or years (e.g., indefinitely).

The eribulin and lenbatinib (or their pharmaceutically acceptable salts such as mesylate salts) generally start on day 1 or may be taken in other ways (e.g., one of the methods mentioned above). Thus, the drug may be administered on days 1 and 8 of day 21, or on day 8 or day 1, day 8, and day 15 of the 28 day cycle. Or one of the drugs (e.g., eribulin, eribulin (or a pharmaceutically acceptable salt thereof) may be administered on a day or 8 day during a 21 day cycle, while other drugs (e.g., (E.g., a pharmaceutically acceptable salt such as valinyl sulphate, valinyl sulphate, or valinyl sulphate) may be administered on days 1, 8, and 15 of day 28. As another option, a combination of eribulin (or a pharmaceutically acceptable salt such as eribulin mesylate ) May be administered intravenously for about 2 minutes to about 5 minutes on days 1 and 8 of a 21 day cycle, whereas lenbactin (or a pharmaceutically acceptable salt thereof, such as lenbatisnib) may be administered intravenously, It may be administered once a day at 4-24 mg starting on the same day as an acceptable salt.

The methods of the invention, along with eribulin and renatintib (or pharmaceutically acceptable salts thereof, such as a mesylate salt), may include the administration of one or more therapeutic agents. The therapeutic agent may be an immunomodulator (for example, an antibody or a vaccine), a chemotherapeutic agent / anticancer agent, an antibacterial agent, a corticosteroid and an anti-inflammatory agent.

The methods of the invention can be used to treat or prevent cancer in a subject (e.g., a human patient) and / or to reduce tumor size. Subjects are those diagnosed with cancer, at risk of developing cancer, in cancer treatment, or in recovery phase after cancer treatment. The methods of the invention may also be used to treat or prevent metastasis and / or recurrence. The treatment method may be a chemotherapy monotherapy and may be used in conjunction with surgical procedures, radiation therapy, and / or resection to remove or reduce tumor size.

The types of cancer that can be treated by the method of the present invention include breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colon cancer, ovarian cancer, endometrial cancer, skin cancer (e.g. melanoma), prostate cancer, brain cancer, head and neck cancer, liver cancer (Eg, rheumatoid arthritis), lymphoid cancer, thyroid cancer, bone cancer (eg, osteosarcoma), and fibrosarcoma.

Kit

The present invention encompasses a container comprising eribulin (or a pharmaceutically acceptable salt thereof, such as an eribulin mesylate) and / or lenbactinib (or a pharmaceutically acceptable salt thereof, such as a lanthabine mesylate) The kit comprising: In such kits, the drug may provide an amount sufficient to treat a cancer patient (e. G., An amount sufficient for single administration or multiple administration). The kit may comprise one or more pharmaceutically acceptable salts such as single-dose eribulin (or a pharmaceutically acceptable salt thereof, such as an erythorbic mesylate) and / or lenbactin (or a pharmaceutically acceptable salt thereof, such as lenbatinib mesylate) ) ≪ / RTI > pharmaceutical composition. Alternatively, devices, devices, and / or diluents may be included in the kit for administration of the pharmaceutical composition. In addition, for the treatment of cancer patients, the kit may include additional instructions such as an instructipn or schedule of administration.

FIG. 1 is a graph showing the anticancer effect of E7080 and E7389 in mouse A375 human malignant melanoma xenograft model. Data are presented as mean ± standard error (n = 6). The arrows on days 17 and 24 after implantation are the treatment start date, the arrow indicates E7389, and the line indicates E7080. iv = intravenous, po = per os (oral), Q1Dx14 = once daily for 14 days, Q7Dx2 = once a week for 2 weeks. * P < 0.05 versus 30 days E7389 3.0 mg / kg single (Dunnett's multiple comparison test after dispersed one-way analysis).
Figure 2 is a graph showing weight change in animals treated with E7389 alone, E7080 alone, and E7389 + E7080. Data are presented as mean ± standard error (n = 6). The arrows on days 17 and 24 after implantation are the treatment start date, the arrow indicates E7389, and the line indicates E7080. iv = intravenous, po = per os (oral), Q1Dx14 = once daily for 14 days, Q7Dx2 = once a week for 2 weeks. Body weight reduction was observed after 3.0 mg / kg E7389 alone and in combination. Partial weight recovery was observed after completion of drug treatment in all mice.
Figure 3 is a graph showing the anticancer effect of E7389 and E7080 in NCI-H1993 (left) or PC-9 (right) human non-small cell lung xenograft mouse models. Data are presented as means ± SD (n = 5). The 0 and 7 day arrows indicate E7389 infusion and the 0-11 day line indicates E7080 administration. iv = intravenous, po = per os (oral), Q1Dx12 = once daily for 12 days, Q7Dx2 = once a week for 2 weeks. * P &lt; 0.05: Combination therapy group vs. Statistical analysis of each monotherapy group (repeatedly measured by ANOVA test).

The present invention can be represented by the following embodiments, but it should not be construed as limiting the scope of the present invention.

Example 1: Effect of combination of E7389 and E7080 in A375 human malignant melanoma xenografted mice

summary

The anti-cancer activity of E7389 (eribulin mesylate) and E7080 (lanthabine mesylate) on intravenous administration of A375 human malignant melanoma xenografting magnetic athymic mouse subcutaneous pre-injection model was measured. E7389 was administered alone at 0.05, 0.2, or 3.0 mg / kg (maximum tolerated dose [MTD]), or in combination with 15 mg / kg E7080 (MTD).

Combined administration of E7389 and E7080 reduced tumors and single administration delayed tumor growth. The addition of 3.0 mg / kg E7389 (Q7Dx2) twice a week / week and 15 mg / kg E7080 (Q1Dx14) every 14 days for 1 day resulted in an additional decrease in animal body weight. However, the weight recovered after the drug treatment was completed.

Experimental Method

Test compound dosage formulations

E7080 was dissolved in WFI at a concentration of 1.5 mg / mL. The E7080 dosing solution was formulated for 7 days. The stock solution was stored at 4 占 폚. 0.5 mg / mL E7389 was diluted to 0.005, 0.02, and 0.3 mg / mL in 3% ETOH under saline. E7389 was formulated to be taken daily.

Measurement of antitumor activity

At 37 ° C in a CO ₂ humidified incubator, A375 human malignant Melanoma cells were cultured as a monolayer in DMEM culture medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin-glutamine. On the day of injection, the cells were trypsinized, washed, and mixed with cold PBS / metrizol 1: 1 (v / v). A375 malignant melanoma cells (5 x ¹⁰⁶ cells / animal) were inoculated into 80 female immunocompromised mice (Mouse / Crl: NU-Foxn1nu; Charles River Laboratories) in a 0.1 mL volume using a 26-gauge needle And subcutaneously injected into the right armpit area.

The experiment consisted of a vehicle-treated control group, a single drug-treated group of E7389 or E7080, and three co-administered drug-treated groups (Table 1). Each group consists of 6 mice, totaling 48 mice. Forty - eight out of eighty were selected by tumor volume and randomly divided into eight groups. After tumor transplantation, the mean tumor volume was about 300 mm ³ at 17 days in each group. After randomization, the drug was administered. E7080 was orally administered daily for 14 days at a volume of 0.1 mL volume / 10 g. E7389 (0.05 mg / kg) was intravenously administered daily for 14 days. In the co-administered group, E7389 was administered 3 hours after oral administration of E7080. 0.2 or 3.0 mg / kg E7389 was administered with Q7Dx2 alone or with E7080 (Q1Dx14). The control group received vehicle (oral administration of WFI daily (Q1Dx14) for 14 days and intravenous 3% ETOH under saline solution as Q7Dx2).

Normal mouse health status was monitored daily. Tumor volume was calculated using the formula (1 x w ² ) / 2 = mm ³ (Mm) using a caliper. 1 and w are the larger and smaller vertical line lengths. Tumor size and body weight were measured twice a week from the first day of drug treatment. Relative body weights were calculated as follows: Body weight = (weight of the day) / (weight of the first day of treatment).

Data were generated with group mean weight and group mean tumor volume at each measurement. The mean ± standard error (SEM) for tumor volume and unweighted weight was calculated for each experiment.

Animals with the longest axis of tumor size ≥20 mm or ulcerated were euthanized before the end of the experiment. This experiment was completed on the 30th day.

A375 Experimental design of anticancer activity of E7389 and E7080 in human malignant melanoma xenograft group Treatment Number of animals A Vehicle (WFI) p.o. Q1Dx14 + 3% ETOH saline i.v. Q7Dx2 6 B E7080 15 mg / kg p.o. Q1Dx14 6 C E7389 0.2 mg / kg i.v. Q7Dx2 6 D E7389 3.0 mg / kg i.v. Q7Dx2 6 E E7389 0.05 mg / kg i.v. Q1Dx14 6 F E7080 15 mg / kg p.o. Q1Dx14 + E7389 0.2 mg / kg i.v. Q7Dx2 6 G E7080 15 mg / kg p.o. Q1Dx14 + E7389 3.0 mg / kg i.v. Q7Dx2 6 H E7080 15 mg / kg p.o. Q1Dx14 + E7389 0.05 mg / kg i.v. Q1Dx14 6

Statistical analysis

Statistical analysis of E7389 3.0 mg / kg single dose and E7080 15 mg / kg combination was performed using ANOVA and Dunnett's multiple comparison experiments. P <0.05 indicates statistical significance. Statistical analysis was performed using Graphpad prism software (version 5).

Experiment result

Figure 1 shows the effect of the combined administration of E7389 and E7080 in human malignant melanoma xenografted mice. At concentrations of up to 3.0 mg / kg (MTD for E7389) and 15 mg / kg (MTD for E7080), a single dose of E7389 or E7080 delayed tumor growth, but did not reduce the tumor. Concomitant administration of E7389 and E7080 enhanced the anticancer activity of E7389 at all concentrations. Tumor growth inhibition was observed in a dose-dependent manner in all co-administered groups (Figure 1). Administration of 3.0 mg / kg E7389 and E7080 resulted in additional weight loss, but weight recovery was restored after the drug treatment was completed (Figure 2).

E7080 was orally administered once per day for 14 days. 0.05 mg / kg E7389 was intravenously administered daily for 14 days. In concomitant administration, E7389 was administered 3 hours after oral administration of E7080. 0.2 or 3.0 mg / kg E7389 was administered as single or combined with Q7Dx2. This experiment was terminated 30 days after xenotransplantation. Concomitant administration of 3.0 mg / kg (Q7Dx2) and 15 mg / kg E7080 (Q1Dx14) and concomitant administration of 0.05 mg / kg E7389 (Q1Dx14) and 15 mg / kg E7080 (Q1Dx14) resulted in decreased tumors.

conclusion

3.0 mg / kg E7389 alone or in combination showed potent antitumor activity in the A375 human malignant melanoma xenograft model. Weight loss was reversible and partially recovered after drug treatment. E7389 was administered at low doses (0.05 mg / kg Q1Dx14) at regular intervals (Q1Dx14) with 15 mg / kg E7080 daily administered, resulting in significant tumor reduction compared with 3.0 mg / kg E7389 single dose.

Example 2: Combination therapy in breast cancer patients

Patients with breast cancer were given E7389 (eribulin mesylate) and E7080 (lanthabine mesylate) in combination. E7389 was administered intravenously at 1.4 mg / m &lt; ² &gt; over 2-5 minutes on days 1 and 8 of the 21-day cycle. E7080 was orally administered at a daily dose of 24 mg / day in a 21-day cycle of E7389 administration. Patients repeated 4-6 cycles depending on factors such as severity of illness and side effects as well as clinical effects. Optionally, administration of E7080 was continued after the end of the E7389 dosing cycle.

Example 3: Effect of E7389 and E7080 co-administration in NCI-H1993 and PC-9 human non-small cell lung cancer xenografted mice

summary

The antitumor effect of the combined administration of intravenous E7389 (eribulin mesylate) and E7080 (lenvatinib mesylate) oral administration was investigated in subcutaneously administered NCI-H1993 or human non-small cell lung cancer xenograft athymic mice. E7389 was administered in combination with 1.5 mg / kg single dose or 10 mg / kg E7080. The combination of E7389 and E7080 showed significantly stronger antitumor activity than single administration.

Experimental Method

Test compound dosage formulations

E7080 was dissolved in DW at a concentration of 1.0 mg / mL. 0.5 mg / mL E7389 was diluted in saline at a concentration of 0.15 mg / mL.

Antitumor activity measurement

NCI-H1993 and PC-9, human non-small cell lung cancer cell lines, were cultured in RPMI-1640 culture medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin-amphotericin at 37 ° C in a 5% CO ₂ humidified incubator Lt; / RTI &gt; On the day of cell inoculation, the cells were trypsinized, collected, washed and mixed with medium / GelTrex 1: 1 (v / v). NCI-H1993 and PC-9 human beings in a 0.1 mL volume were injected into the right armpit area of an immunocompromised magnetic mouse (BALB / c Slc nu / nu; Japan SLC, Inc.) using 26- - Small cell lung cancer cells (10 x 10 ⁶ cells / animal) were subcutaneously injected.

This study consisted of a non-treated group, a single drug-treated group of E7389 (1.5 mg / kg) or E7080 (10 mg / kg), and a coadministered group, each group containing 5 mice. Mice were screened according to tumor size and approximately 200 mm ³ (NCI-H1993: 191 mm ³ , PC-9: 227 mm ³ ) were injected on day 10 (NCI-H1993) or day 8 (PC- Of the tumor volume. After sorting, drug treatment was started. E7389 (1.5 mg / kg) was intravenously administered weekly for 2 weeks (Q7Dx2). E7080 was orally administered daily for 12 days (Q1Dx12). The drugs were administered in a volume of 0.1 mL per 10 g body weight.

Tumor volume was measured with a caliper (mm) using the following formula.

Tumor volume (mm ³ ) = Length (mm) x Width ² (mm ² ) x 1/2

Length: The longest diameter in the tumor

Width: Diameter perpendicular to length

Tumor volume was calculated as mean ± standard deviation in each experimental group.

Statistical analysis

A two-way RM-ANOVA test was used for statistical analysis of the single-dose and co-administered groups or the control group. P <0.05 means statistical significance. Statistical analysis was performed using Graphpad prism software (version 6.02).

Experiment result

Figure 3 shows the combined effect of E7389 and E7080 in NCI-H1993 (left) or PC-9 (right) human non-small cell lung cancer xenografted mice. Single doses of E7389 (1.5 mg / kg) or E7080 (10 mg / kg) showed significant antitumor activity in the xenograft model. Concomitant administration of E7389 and E7080 significantly increased anti-tumor activity over single administration.

conclusion

The combination of E7389 and E7080 showed more potent antitumor activity than single administration.

Specific Example

A specific embodiment of the present invention is as follows:

[1] A method of treating a subject having cancer or at risk of developing cancer, the method comprising: (i) eribulin or a pharmaceutically acceptable salt thereof; and (ii) RTI ID = 0.0 &gt; acceptable salt. &Lt; / RTI &gt;

[2] In the method of [1] above, the subject is a human patient.

[3] The method according to the above [1] or [2], wherein the subject is a subject diagnosed with cancer, treated with cancer, or recovered after cancer treatment.

[4] The method according to any one of [1] to [3], wherein the cancer is a primary tumor.

[5] The method according to any one of [1] to [3], wherein the cancer is metastatic cancer.

[6] The method according to any one of [1] to [5], wherein the cancer is a solid tumor.

(7) The method according to any one of (1) to (6) above, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colon cancer, ovarian cancer, endometrial cancer, (Cancer), brain cancer, head and neck cancer, liver cancer, kidney cancer, bladder cancer, gastric cancer, gastric cancer, blood cancer (e.g., leukemia), lymphoma, thyroid cancer, osteoma (osteosarcoma) and fibrosarcoma.

[8] In any one of the above-mentioned methods [1] to [7], the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[9] In any one of the above-mentioned methods [1] to [8], the above-mentioned Lenvatib or a pharmaceutically acceptable salt thereof is lanbatinib mesylate.

[10] In any one of the above-mentioned methods [1] to [8], the eribulin or a pharmaceutically acceptable salt thereof is administered intravenously.

[11] The method according to the above [10], wherein the intravenous administration is performed for 1 minute to about 20 minutes.

[12] In the method of [11], the intravenous administration is performed for 2 minutes to about 5 minutes.

[13] In any one of the above-mentioned methods [1] to [12], eribulin or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.1 mg / m ² to about 20 mg / m ² .

[14] In the method of [13], the eribulin or a pharmaceutically acceptable salt thereof is administered in an amount of 1.4 mg / m ² or 1.1 mg / m ² .

[15] In any one of the above-mentioned methods [1] to [14], the eribulin or a pharmaceutically acceptable salt thereof is administered once every 1 day and 8 days in 21-day cycle.

[16] In any one of the above-mentioned methods [1] to [15], the above-mentioned renatavidin or a pharmaceutically acceptable salt thereof is orally administered.

[17] The method according to any one of [1] to [16], wherein the renativinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.1 mg to about 100 mg.

[18] In the method of [17] above, the Lenvatib or a pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg to about 24 mg.

[19] In any one of the above-mentioned methods [1] to [18], the above-mentioned Lenvatib or a pharmaceutically acceptable salt thereof is administered daily.

[20] In any one of the above-mentioned methods [1] to [19], the eribulin or a pharmaceutically acceptable salt thereof and lenbatimib or a pharmaceutically acceptable salt thereof are administered mainly simultaneously or sequentially.

[21] The method according to any one of [1] to [20], wherein the treatment comprises (i) reducing the number of cancer cells; (Ii) reduce the tumor volume; (Iii) increase the tumor regression rate; (Iv) reducing or delaying cancer cell penetration into the surrounding organs; (V) reduce or delay tumor metastasis; (Vi) reducing or inhibiting tumor growth; (Iii) inhibiting or delaying the development and / or recurrence of cancer and / or prolonging the disease-free or tumor-free survival time; (Iii) increase the overall survival time; (Iii) reduce the frequency of treatment; And / or (x) relieves one or more symptoms associated with cancer.

[22] A method of reducing tumor size in a subject, said method comprising administering (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenbatimib or a pharmaceutically acceptable salt thereof .

[23] A kit for use in the treatment of cancer, tumor size reduction, or induction of an immune response against a tumor in a subject, said kit comprising (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) ) &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

[24] In the kit of [23], the (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenbatinib or a pharmaceutically acceptable salt thereof are dosage forms.

[25] An eribulin or a pharmaceutically acceptable salt thereof for use in a method of treating a subject having cancer or at risk of developing cancer, said compound being selected from the group consisting of lenbatinib or a pharmaceutically acceptable salt thereof &Lt; / RTI &gt;

[26] In the eribulin of the above-mentioned [25] or a pharmaceutically acceptable salt thereof, the compound and the lenbactinib or a pharmaceutically acceptable salt thereof are administered mainly simultaneously or sequentially.

[27] In the eribulin of the above-mentioned [25] or [26] or a pharmaceutically acceptable salt thereof, the compound is an eriburyl mesylate.

[28] A method for treating a subject having cancer or a subject at risk of developing cancer, comprising administering to said subject a therapeutically effective amount of erbulinine or a pharmaceutically acceptable salt thereof, &Lt; / RTI &gt;

[29] In [28] the above-mentioned compound and the eribulin or a pharmaceutically acceptable salt thereof, are administered simultaneously or sequentially.

[30] The compound of [28] or [29], wherein the compound is lenbital nimesilate.

[31] A pharmaceutical composition for treating a subject having or at risk of developing cancer, comprising eribulin or a pharmaceutically acceptable salt thereof, wherein the composition is selected from the group consisting of lenbactinib or its pharmaceutical Lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt.

[32] A pharmaceutical composition for the treatment of a subject having or at risk of developing cancer, which comprises renatintinib or a pharmaceutically acceptable salt thereof, wherein the composition comprises eribulin or its pharmaceutical Lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt.

[33] In the pharmaceutical composition of [31] or [32], the eribulin or a pharmaceutically acceptable salt thereof and the lenbactinib or a pharmaceutically acceptable salt thereof are administered mainly simultaneously or sequentially .

[34] In any one of the above-mentioned [31] to [33], the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[35] In any one of the above-mentioned [31] to [33], the above-mentioned Lenvatib or a pharmaceutically acceptable salt thereof is lanbatinib mesylate.

[36] A pharmaceutical composition comprising (i) eribulin or a pharmaceutically acceptable salt thereof for treating a subject having cancer or at risk for developing cancer or for reducing tumor size, and (ii) Use of a pharmaceutically acceptable salt.

(I) eribulin or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a subject having cancer or at risk of developing cancer or for reducing tumor size; ) &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

The various embodiments of item [2] to [21] (method) are applicable to item [36] and [37] (application).

Other Embodiments

While the present invention has been described in connection with the foregoing specific embodiments, it can be modified and the present application includes any modifications, uses, or applications of the following inventions, and in general, principles of the invention. Also included are known or conventional techniques to which the present invention belongs which is not disclosed in the present invention, and these techniques can be applied to the essential features of the present invention described above.

All publications or patent applications mentioned in this specification are herein incorporated by reference and the independent publications or patent applications specifically and individually are incorporated by reference in their entirety.

The use of singular terms such as &quot; a &quot; and &quot; the &quot; does not exclude plural forms unless the contrary is indicated. Likewise, the use of plural terms does not exclude the representation of the singular form. Other embodiments are within the scope of the following claims.

Claims (37)

A method of treating a subject with cancer or at risk of developing cancer, said method comprising the steps of (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenvatinib) or a pharmaceutically acceptable salt thereof.
8. The method of claim 1, wherein the subject is a human patient.
3. The method according to claim 1 or 2, wherein said subject is a subject diagnosed with cancer, treated with cancer, or is in recovery phase after cancer treatment.
4. The method according to any one of claims 1 to 3, wherein the cancer is a primary tumor.
4. The method according to any one of claims 1 to 3, wherein the cancer is metastatic cancer.
6. The method according to any one of claims 1 to 5, wherein the cancer is a solid tumor.
7. The method of any one of claims 1 to 6 wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colon cancer, ovarian cancer, endometrial cancer, skin cancer (e.g. melanoma), prostate cancer, Wherein the cancer is selected from the group consisting of head and neck cancer, liver cancer, renal cancer, bladder cancer, gastric cancer, gastric cancer, blood cancer (e.g. leukemia), lymphoma, thyroid cancer, bone cancer (e.g. osteosarcoma) and fibrosarcoma.
8. A method according to any one of claims 1 to 7, wherein the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
9. The method according to any one of claims 1 to 8, wherein the lenbatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.
10. A method according to any one of claims 1 to 9, wherein said eribulin or a pharmaceutically acceptable salt thereof is administered intravenously.
11. The method of claim 10, wherein the intravenous administration is performed for 1 minute to about 20 minutes.
12. The method of claim 11, wherein the intravenous administration is conducted for 2 minutes to about 5 minutes.
13. The method according to any one of claims 1 to 12, wherein the eribulin or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.1 mg / m ² to about 20 mg / m ² .
14. The method according to claim 13, wherein the eribulin or a pharmaceutically acceptable salt thereof is administered in an amount of 1.4 mg / m ² or 1.1 mg / m ² .
15. The method according to any one of claims 1 to 14, wherein the eribulin or a pharmaceutically acceptable salt thereof is administered once every 1 day and 8 days in 21-day cycle.
16. The method according to any one of claims 1 to 15, wherein the lenbatinib or a pharmaceutically acceptable salt thereof is orally administered.
17. The method according to any one of claims 1 to 16, wherein the lenbatinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.1 mg to about 100 mg.
18. The method of claim 17, wherein the renatotinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg to about 24 mg.
19. The method according to any one of claims 1 to 18, wherein said lenbatinib or a pharmaceutically acceptable salt thereof is administered daily.
The therapeutic method according to any one of claims 1 to 19, wherein said eribulin or a pharmaceutically acceptable salt thereof and lenbatinib or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially .
21. The method of any one of claims 1 to 20, wherein said treatment comprises: (i) reducing the number of cancer cells; (Ii) reduce the tumor volume; (Iii) increase the tumor regression rate; (Iv) reducing or delaying cancer cell penetration into the surrounding organs; (V) reduce or delay tumor metastasis; (Vi) reducing or inhibiting tumor growth; (Iii) inhibiting or delaying the development and / or recurrence of cancer and / or prolonging the disease-free or tumor-free survival time; (Iii) increase the overall survival time; (Iii) reduce the frequency of treatment; And / or (x) alleviating one or more symptoms associated with cancer.
A method of reducing tumor size in a subject, said method comprising the steps of (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenvatinib or a pharmaceutical composition thereof, Lt; RTI ID = 0.0 &gt; acceptable salt. &Lt; / RTI &gt;
A kit for use in the treatment or prophylaxis of cancer treatment, tumor size reduction or an immune response to a tumor in a subject, said kit comprising (i) eribulin or a pharmaceutically acceptable salt thereof, And (ii) lenvatinib or a pharmaceutically acceptable salt thereof.
24. The kit according to claim 23, wherein the (i) eribulin or a pharmaceutically acceptable salt thereof and (ii) lenbatinib or a pharmaceutically acceptable salt thereof are in a dosage form.
An eribulin or a pharmaceutically acceptable salt thereof for use in a method of treating a subject having cancer or at risk of developing cancer, said compound being selected from the group consisting of lenvatinib, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 25, wherein said compound and said lanbatimib or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.
27. The compound of claim 25 or 26, wherein the compound is an eribulin mesylate.
Or a pharmaceutically acceptable salt thereof for use in a method of treating a subject with cancer or at risk of developing cancer, said compound being selected from the group consisting of eribulin or a pharmaceutically acceptable salt thereof. &Lt; RTI ID = 0.0 &gt;&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
29. The compound of claim 28, wherein said compound and said eribulin or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.
30. A compound according to claim 28 or 29, wherein said compound is lenvatinib mesylate.
A pharmaceutical composition for treating a subject having cancer or at risk of developing cancer, comprising eribulin or a pharmaceutically acceptable salt thereof, wherein the composition is selected from the group consisting of lenbitalip lenvatinib, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for the treatment of a subject having or at risk of developing cancer, comprising lenvatinib or a pharmaceutically acceptable salt thereof, wherein the composition is selected from the group consisting of eribulin ( 0.0 &gt; eribulin &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
33. The pharmaceutical composition according to claim 31 or 32, wherein the eribulin or a pharmaceutically acceptable salt thereof and the lenbactinib or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.
34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.
(I) eribulin or a pharmaceutically acceptable salt thereof for treating a subject having cancer or at risk for developing cancer or for reducing tumor size and (ii) (lenvatinib) or a pharmaceutically acceptable salt thereof.
(I) eribulin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a subject having cancer or at risk of developing cancer or for reducing tumor size, And (ii) the use of lenvatinib or a pharmaceutically acceptable salt thereof.

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